Update on Familial Adenomatous Polyposis-Associated Desmoid Tumors

Abstract

Desmoid tumors (DT) represent the second high risk of tumor in familial adenomatous polyposis (FAP) patients. Although FAP-associated DTs (FAP-DT) are caused by germline mutations in the adenomatous polyposis coli (APC) gene, extracolonic manifestations, sex, family history, genotype, and the ileal pouch anal anastomosis procedure are all linked to the development of DTs in FAP patients. Multidisciplinary management has replaced aggressive surgery as the preferred treatment of DTs. There is growing evidence to support the use of active surveillance strategy as first-line treatment for FAP-DT patients. Radiotherapy for intra-abdominal desmoids is now rarely used because of severe late toxicity. Pharmacotherapy, however, represents a promising future with the improvement of traditional cytotoxic drugs and the investigation of targeted drugs. Although nonsurgery treatment has been used widely nowadays, surgery remains the mainstay when symptomatic or life-threatening DTs are present. Further research will be needed for more optimal clinical practice.

Desmoid tumors (DT), also called aggressive fibromatosis, are rare mononal, fibroblastic proliferation tumors. It usually appears to infiltrate locally but does not metastasize. Despite the lack of metastasizing tendency, it presents an unpredictable landscape in clinical practice. Unlike most DTs caused by CTNNB1 mutation, approximately 30% of DTs caused by adenomatous polyposis coli (APC) germline mutation are associated with familial adenomatous polyposis (FAP). ¹ This article reviews update on FAP-associated DTs (FAP-DT) in recent years.

Risk Factors

Extracolonic manifestations, sex, family history, surgery trauma, and genotype are considered risk factors for the development of DTs. Extracolonic manifestations include those associated with Gardner's syndrome, such as osteomas, epidermoid cysts, and extra teeth. ² According to a meta-analysis, ³ while females are one and half times more likely to develop DTs in FAP patients, a positive family history of DTs is the most significant risk factor (odds ratio [OR] 7.02, p  < 0.001). Previous abdominal surgery (OR 3.35, p  = 0.01) is also implicated. In terms of the genotype, this meta-analysis reveals that the OR for developing DTs with mutations 3′ of 1399 is 4.37 ( p  < 0.001). Notably, a recent study demonstrates that DTs may develop in FAP patients regardless of the APC mutation site, while the incidence and severity of the DTs are related to the site of the mutation, with an increasing propensity and worse staging in those with mutations 3′ of codon 1399. ⁴ Recently, it is confirmed that extracolonic manifestations, family history of DTs, and mutation location are associated with higher risk, along with the recognition of ileal pouch anal anastomosis (IPAA) procedure as a new risk factor. ⁵

Clinical Presentation and Diagnosis

While DTs usually presenting with painless growth can occur almost anywhere in the body, the incidence of intra-abdomen location is increased severalfold in FAP-DT, and complications such as obstruction and ischemia of intestine can occur.

The diagnosis of FAP-DT relies on the biopsy and FAP history, and computed tomography (CT) and magnetic resonance imaging play an important role in determining the relationship between the tumor and adjacent structures. It is reported that positron emission tomography/CT has the ability to distinguish between recurrent cancer and DTs in FAP patients, with moderately intense in recurrent cancer versus mild uptake in DTs. ⁶

Traditionally, to determine if a DT might be associated with underlying FAP, affected individuals are often referred for colonoscopy, but this strategy seems to be controversial because of the low rate of detection. ⁷ Investigators have identified multiple risk factors, including age less than 40 years old, multifocal disease, and unknown family history or first-degree relatives with colorectal neoplasms, with greater likelihood of subsequent FAP diagnosis upon colonoscopy. ⁸ According to the consensus published by the Desmoid Tumour Working Group and a recent study, it is beneficial to conduct CTNNB1 mutation analysis in newly diagnosed DTs and additional testing (APC or colonoscopy) if the results are CTNNB1 wild-type, ^{9 10} since mutations in CTNNB1 and APC are mutually exclusive. ¹¹

Prevention

It is obvious that if the associated risk factors can be avoided or controlled, the likelihood of developing a DT in individuals with FAP should be as much as possible reduced. However, other than surgical procedure, the majority of these risk factors are powerless to interfere.

Considering surgery trauma plays an important role in the development of DTs, prophylactic colectomy should be postponed if possible when associated risk factors (female, APC germline mutation beyond codon 1399, family history, and extracolonic manifestations) are present in FAP patients, particularly when female patients present with a 3′ APC mutation. ^{3 4} However, when surgery is necessary, IPAA should be avoided as much as possible in case of the development of DTs. ⁵

Therefore, clinicians should also pay more attention to the identification of risk factors associated with DTs while managing FAP patients.

Treatment

The treatment of DTs is generally guided in regard to the anatomical site and the overall conditions of patients. In the setting of the abdominal location, where FAP patients are most prevalent, treatment decisions are different with regard to abdominal wall DTs and intra-abdominal DTs. As depicted in the treatment algorithm ( Fig. 1 ) recommended by the Desmoid Tumor Working Group, ⁹ in the case of progression after active surveillance, surgery is the first line of treatment for abdominal wall DTs, while pharmacological treatment should be considered as the priority treatment for intra-abdominal DTs. Meanwhile, radiotherapy may be an option when medication or surgery is not appropriate for patients.

Fig. 1.

Treatment algorithm recommended by The Desmoid Tumor Working Group. ¹⁰ Sx, surgery; Sx*, surgery is an option if morbidity is limited; MTx, medical treatment; RTx, radiotherapy.

Active Surveillance

Active surveillance has become the first-line treatment, with the Desmoid Tumor Working Group having related consensus. ⁹ The National Comprehensive Cancer Network also recommends that patients with DTs undergo an initial period of observation in the absence of progressive, morbid, or symptomatic disease. ¹²

While the majority of the evidence comes from studies that exclude FAP-DT, one study shows that in 26 patients with FAP-associated intra-abdominal DTs (17 active surveillance and 9 pharmacological treatment), the 10-year progression-free survival (PFS) rate is 49% for nonsurgical treatment. ¹³ Another study with 81 FAP-DT patients reveals that after prolonged follow-up, over half of abdominal DT patients who initially received observation required no intervention. ¹⁴

Based on tumor size, growth rate, symptoms, and complications, researchers have classified FAP-associated intra-abdominal DTs into four stages ( Table 1 ). Patients in stage I/II can be treated with active surveillance with or without low toxicity drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and hormones; while patients in stage III/IV are advised to use a combination of pharmacological therapy and surgical intervention. ^{15 16}

Table 1. Desmoid tumors staging system established by Church et al ¹⁵ .

Stage
I	Asymptomatic, < 10 cm maximum diameter, and not growing
II	Mildly symptomatic, < 10 cm maximum diameter, and not growing
III	Moderately symptomatic, or bowel/ureteric obstruction, or 10 to 20 cm, or slowly growing
IV	Severely symptomatic, septic complications such as fistula and abscess, or > 20 cm or rapidly growing
	Mildly symptomatic: sensation of mass, pain, but no restriction Moderately symptomatic: sensation of mass, pain; restrictive but not hospitalized Severely symptomatic: sensation of mass, pain; restrictive and hospitalized

Surgery

The cornerstone in the treatment of DTs used to be surgery, but this is no longer the case as the clinical benefits of active surveillance and pharmaceutical therapy are increasingly obvious. When it comes to FAP-DT, they often affect the mesentery, which can result in life-threatening complications, and make the choice of surgery more controversial. According to one study, the 10-year PFS rates for surgical and nonsurgical treatment (active surveillance or pharmacological treatment) for FAP-associated intra-abdominal DTs are 33 and 49%, respectively. ¹³ It seems that choosing surgery means worse outcomes. However, in the case of severe complications, such as perforations and abscesses, surgery is indicated. It suggests that surgical treatment should be cautiously chosen for FAP-associated intra-abdominal DT patients.

Most FAP-DT patients usually have intra-abdominal DTs, which may restrict the length of small bowel mesentery and disturb the implementation of IPAA. Interestingly, it is reported that in FAP patients, IPAA is linked to a higher “desmoidogenic” risk than ileorectal anastomosis (IRA). ^{5 17} But whether IPAA is more likely than IRA to increase “desmoidogenic” risk remains controversial. According to a recent meta-analysis, IPAA does not increase the “desmoidogenic” risk in FAP patients after surgery. ¹⁸

Another contentious subject is the postoperative recurrence rate. Even if the resection margin is broadly negative, the postoperative recurrence rate of DTs can be as high as 50%, and intra-abdominal DTs have a higher postoperative recurrence rate of 57 to 88%. ^{19 20} An 8-year observational study shows that FAP history is an independent risk factor of postoperative recurrence, with a worse PFS compared with those without FAP history, a limitation in this study is that there are only three patients in the FAP group. ²¹ Remarkably, studies that only include extra-abdominal DTs reveal larger tumor size (> 10 cm) is associated with higher postoperative recurrence rates. ^{22 23} It will be of great value if the same tendency also applies to intra-abdominal DTs.

Meanwhile, successful small bowel transplantation after total bowel resection has also been reported in patients with intra-abdominal DTs recently, ^{24 25 26} bringing hope to more patients.

Radiotherapy

Research has indicated that radiotherapy can help patients with DTs achieve better local control, and that radiotherapy alone or in combination with postoperative radiotherapy can help approximately 70 to 80% of those patients achieve long-term local control.

Previous studies on pediatric or young adults show worse local management of DTs. Recent data on radiotherapy for DTs still supports this. According to one study, individuals under the age of 20 at diagnosis had a much lower 5-year local control rate than those over the age of 40 (72% vs. 97%). ²⁷ Another study also confirmed that younger age (≤ 30 years) is associated with worse outcome. ²⁸

These data, however, include many non-FAP DTs patients, therefore cannot totally be applied to FAP-DT patients. In contrast, late toxicity is especially severe in FAP-associated DTs patients receiving radiotherapy, including gastrointestinal fistula, perforation, and abscess. ^{29 30} Therefore, radiotherapy on FAP-DT patients should be only initiated when other options have been exploited.

Pharmacological Treatment

In recent years, the pharmacological treatment for DTs has evolved to include hormones, NSAIDs, tyrosine kinase inhibitors (TKIs), cytotoxic drugs, and so on. However, more fruitful studies are needed due to the lack of evidence for the pharmacological treatment of FAP-DT patients.

Hormones/NSAIDs

Estrogen receptor-β and COX2 expression are frequently present in DTs, suggesting that hormone therapy with/without NSAIDs may be effective in DTs.

Notably, the efficacy of hormone-based regimens has been reported in small case-cohort studies. ^{31 32} The effectiveness of hormones combined with NSAIDs has recently been supported by a long-term observational study that includes 55 FAP-DT patients, with 23 (41.8%) of them reaching objective response. ³³ Although the studies have shown that approximately 40% of desmoids show objective response to this strategy, it is difficult to be sure that this is truly an effect of the drug treatment because spontaneous remission may occur. However, a prospective study shows limited benefits using tamoxifen combined with sulforaphane, with only 5 patients (8%) reaching objective response and a 2-year PFS rate of 36%. ³⁴

TKIs

TKIs have demonstrated efficacy in phase II/III clinical trials; however, the treatment should be selected carefully because these trials include patients with sporadic DTs. ³⁵

In a phase II trial conducted by French Sarcoma Group, the 1-year PFS rate is 67% (but only 6 are FAP-DT patients). ³⁶ In another recent study, 16 of 49 patients (33%) receiving sorafenib reached objective response after a median follow-up of 27.2 months, compared with 7 of 35 patients (20%) in the placebo group, and the 2-year PFS rate for sorafenib is significantly higher (81% vs. 36%). ³⁷ However, this study did not specify the FAP history of these patients. Other TKIs, such as pazopanib and sunitinib, ^{38 39} have also resulted in successful cases in FAP-DT patients.

According to recent studies on the molecular mechanisms of TKIs, sorafenib induces death in DT cells and stromal cells by inducing ferroptosis and apoptosis. ^{40 41} Investigators also demonstrated that DT patients receiving imatinib have different levels of HES1, which is regulated by NOTCH2. Moreover, it can be used to recognize patients who can respond to imatinib. ⁴²

Cytotoxic Drugs

Clinically, vincristine and methotrexate, referred to as “low-dose chemotherapy,” and a more aggressive strategy with anthracyclines, are the two primary cytotoxic drug regimens.

The objective response rates of vincristine in combination with methotrexate are approximately 30 to 50% in non-FAP DT patients, but the long-term usage of vincristine-containing regimens are limited by adverse effects like pulmonary fibrosis and liver injury. Large clinical studies have demonstrated that vincristine-containing treatment is well tolerated and beneficial even with shorter treatment duration. According to a retrospective study, the 2-year PFS rate could achieve 86% after a median treatment duration of only 6.7 months with oral vincristine, and the time to treatment failure did neither differ in patients with or without FAP. ⁴³ The best outcomes of partial response and stable disease have been achieved in 20 cases (54%) and 15 cases (41%), respectively, in another retrospective series involving 37 FAP-DT patients treated with vincristine in combination with methotrexate, with the median PFS reaching 6.5 years. ⁴⁴ Notably, in a prospective study of 72 DT patients (but only 11 patients are associated with FAP history), the PFS rates in the pazopanib group are 85.6 and 67.2% at 1 and 2 years, respectively, compared with 79.0 and 79.0% in the vincristine-methotrexate chemotherapy group. ³⁸

Anthracycline-containing regimens for the treatment of FAP-DT have better outcomes according to previous studies; however, due to cardiotoxicity, they are mostly used in DTs that are potentially life-threatening. ^{13 45 46} The new generation of anthracycline, doxorubicin liposome, is far less cardiotoxic than other anthracyclines, but there is a lack of data to confirm its efficacy in FAP-DT.

Case reports or retrospective studies are reporting other cytotoxic agents including gemcitabine and cyclophosphamide, which are limited in clinical practice.

Other Drugs

Nirogacestat (PF-03084014), an oral gamma-secretase inhibitor, has been reported to be promising for the treatment of FAP-DT. Two patients achieved excellent and prolonged response while one patient experienced progression in a phase I study that includes three FAP-DT patients receiving PF-03084014. ⁴⁷ In a phase II study including three FAP-DT patients, disease progression is not detected after a median follow-up time of 25 months. ⁴⁸ Another report also includes three FAP-DT patients, after an average of 11.0 months, two of them achieved stable disease, and the other patient had disease progression after partial response. ⁴⁹

In recent years, tazemetostat (EZH2 inhibitor) is found to have therapeutic effects on DTs in animal models, and in vitro experiments reveal that tazemetostat could directly inhibit the transcription of Wnt/β-catenin pathway in human sclerofibrosarcoma cells. ⁵⁰

It is found that DTs lack relevant immune markers and almost all specimen tumor cells are negative for PD-L1, and PD-1 is only partially expressed in lymphocytes surrounding the tumor. ⁵¹ This suggests that immune checkpoint inhibitors may not be indicated for the treatment of DTs.

Prospective and Conclusion

Due to the low prevalence, many of the reported studies are small case series, making the management of DTs controversial. However, it is undeniable that the validity of active surveillance strategy and targeted drugs indeed shed more light on the treatment of DTs. Meanwhile, the current studies do not adequately distinguish between sporadic and FAP-associated desmoid disease, requiring doctors to read these data exquisitely. So the challenge is that there is still a lack of evidence for clinicians to precisely recognize available patients, making the conduction of randomized, controlled trials more urgent.

Though the treatment paradigm of DTs has shifted in recent years from active intervention to initial observation, surgical treatment still shines in the presence of progressive, morbid, or symptomatic disease. Considering the postoperative recurrence and surgical trauma, more effective factors which can indicate or contradict surgery are urgently needed. Furthermore, with the rapid progress of pharmacological treatment, it may be extremely beneficial if the combination of surgery with drugs (whether preoperative or postoperative) can work.

Notably, previous studies subdivide patients into four stages according to tumor size, growth rate, symptoms, and complications; however, it is rarely used in clinical practice because of limited applicability. Therefore, a key point in the future is to pay more attention to improving the staging and classification of DTs. What is more, given that FAP-DT patients are typically young and tend to be anxious, considerable guidance is crucially needed.

In conclusion, considerable advances have been made in FAP-DT in recent years, and further research in different aspects of FAP-DT management will be needed to optimize clinical practice.

Funding Statement

Funding None.